The present invention relates to certain phenalkyloxy-phenyl derivatives of formula I and analogs, to a process for preparing such compounds, having the utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.
Insulin resistance, defined as reduced sensitivity to the actions of insulin in the whole body or individual tissues such as skeletal muscle, myocardium, fat and liver prevail in many individuals with or without diabetes mellitus. The insulin resistance syndrome, IRS, refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinemia, possibly type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations, the presence of small, dense LDL (Low Density Lipoprotein) particles and reduced fibrinolysis.
Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In non-insulin dependent diabetes mellitus these atherosclerosis related conditions cause up to 80% of all deaths.
In clinical medicine there is at present only limited awareness of the need to increase the insulin sensitivity in IRS and thus to correct the dyslipidemia which is considered to cause the accelerated progress of atherosclerosis.
Furthermore there is at present no pharmacotherapy available to adequately correct the metabolic disorders associated with IRS. To date, the treatment of type 2 diabetes mellitus has been focused on correction of the deranged control of carbohydrate metabolism associated with the disease. Stimulation of endogenous insulin secretion by means of secretagogues, like sulphonylureas, and if necessary administration of exogenous insulin are methods frequently used to normalise blood sugar but that will, if anything, further enhance insulin resistance and will not correct the other manifestations of IRS nor reduce cardiovascular morbidity and mortality. In addition such treatment involves a significant risk of hypoglycemia with associated complications.
Other therapeutic strategies have focused on aberrations in glucose metabolism or absorption, including biguanides, such as methformin, or glucosidase inhibitors, such as acarbose. Although these agents have been efficacious to a degree, their limited clinical effect is associated with side effects.
A novel therapeutic strategy involves the use of insulin sensitising agents, such as the thiazolidinediones which at least in part mediate their effects via an agonistic action on nuclear receptors. Ciglitazone is the prototype in this class. In animal models of IRS these compounds seem to correct insulin resistance and the associated hypertriglyceridaemia and hyperinsulinemia, as well as hyperglycaemia in diabetes, by improving insulin sensitivity via an effect on lipid transport and handling primarily in adipocytes, leading to enhanced insulin action in skeletal muscle, liver and adipose tissue.
Ciglitazone as well as later described thiazolidinediones in clinical development either have been discontinued reportedly due to unacceptable toxicity or show inadequate potency. Therefore there is a need for new and better compounds with insulin sensitising properties.
Other therapeutic strategies have focused on aberrations in glucose metabolism or absorption, including biguanides, such as methformin, or glucosidase inhibitors, such as acarbose. Although these agents have been efficacious to a degree, their limited clinical effect is associated with side effects.
A novel therapeutic strategy involves the use of insulin sensitising agents, such as the thiazolidinediones which at least in part mediate their effects via an agonistic action on nuclear receptors. Ciglitazone is the prototype in this class. In animal models of IRS these compounds seem to correct insulin resistance and the associated hypertriglyceridemia and hyperinsulinemia, as well as hyperglycemia in diabetes, by improving insulin sensitivity via an effect on lipid transport and handling, leading to enhanced insulin action in skeletal muscle, liver and adipose tissue.
Ciglitazone as well as later described thiazolidinediones in clinical development either have been discontinued reportedly due to unacceptable toxicity or show inadequate potency.
Therefore there is a need for new and better compounds with insulin sensitising properties.
The invention relates to compounds of the general formula (I) 
and stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof, in which formula
A is situated in the ortho, meta or para position and represents 
R is cyano, when X is O, and when X is 1 then R is;
xe2x80x94BRa or SCORa, wherein B is O, S, SO or SO, (preferably B is O or S), wherein Ra represents hydrogen, alkyl, aryl or alkylaryl (preferably Ra is selected from hydrogen, alkyl and alkyaryl) and wherein the alkyl, aryl or alkylaryl group is optionally substituted one or more times by Rb, wherein Rb represents alkyl, aryl, alkylaryl, cyano, xe2x80x94NRcRc, xe2x95x90O, halogen, xe2x80x94OH, xe2x80x94SH, xe2x80x94Oalkyl, xe2x80x94Oaryl, xe2x80x94Oalkylaryl, xe2x80x94CORc, xe2x80x94SRd, xe2x80x94SORd, or xe2x80x94SO2Rd (preferably Rb is selected from alkyl, aryl, alkylaryl, cyano, xe2x80x94NH2, xe2x95x90O, halogen and xe2x80x94OH), wherein Rc represents hydrogen, alkyl, aryl or alkylaryl and Rd represents alkyl, aryl or alkylaryl;
xe2x80x94BB1Ra, wherein B1 is O when B is S, SO or SO2 or B1 is S, SO or SO2 when B is O, and wherein B and Ra are as defined above;
or alternatively R is xe2x80x94NRaRa, wherein each Ra is the same or different and wherein Ra is defined above;
R2 represents alkyl, halogen (preferably bromo, chloro or iodo), aryl, alkylaryl, alkenyl, alkynyl, nitro or cyano and wherein the alky, aryl, alkenyl, alkylaryl and alkynyl group is optionally substituted by Rb, wherein Rb is as defined above;
xe2x80x94BRa wherein B and Ra are as defined above;
xe2x80x94SO2NRaRf, wherein Rf represents hydrogen, alkyl, acyl, aryl or alkylaryl and Ra is as defined above;
xe2x80x94SO2ORa, wherein Ra is as defined above;
xe2x80x94OCONRfRa, wherein Rf and Ra are as defined above;
xe2x80x94NRcCOORd, wherein Rc and Rd are as defined above;
xe2x80x94NRcCORa, wherein Rc and Rd are as defined above;
xe2x80x94CONRcRa, wherein Rc and Ra are as defined above;
xe2x80x94NRcSO2Rd, wherein Ra and Rd are as defined above;
xe2x80x94NRcCONRaRk, wherein Ra and Rc are as defined above and Rk represents hydrogen, alkyl, aryl, or alkylaryl;
alternatively R2 is xe2x80x94NRcRa, wherein Rc and Rd are as defined above;
R1, R3 and R4 are the same or different and each represents hydrogen, alkyl, aryl, alkenyl, alkynyl, cyano, halogen or alkylaryl (preferably R1, R3 and R4 are independently selected from hydrogen or alkyl, ideally R1, R3 and R4 are hydrogen) wherein the alkyl, aryl, alkenyl or alkynyl group is optionally substituted by Rb;
n is an integer from 1 to 6 (preferably n is an integer from 1 to 3, ideally n is 1);
X is an integer 0 or 1 (preferably X is 1);
m is an integer 0 or 1 (preferably m is 1);
D is situated in the ortho, meta or para position (preferably D is situated in the para position) and represents alkyl, acyl, aryl, alkylaryl, halogen, xe2x80x94CN and NO2, wherein the alkyl, aryl, or alkylaryl group is optionally substituted by Rb;
xe2x80x94NRcCOORa, wherein Rc and Ra are as defined above;
xe2x80x94NRcCORa, wherein Rc and Ra are as defined above;
xe2x80x94NRcRa, wherein Rc and Ra are as defined above;
xe2x80x94NRcSO2Rd, wherein Rc and Rd are as defined above;
xe2x80x94NRcCONRkRc, wherein Ra, Rc and Rk are as defined above;
xe2x80x94NRcCSNRaRk, wherein Ra, Rc and Rk are as defined above;
xe2x80x94ORa, wherein Ra is as defined above;
xe2x80x94OSO2Rd, wherein Rd is as defined above;
xe2x80x94SO2Rd, wherein Rd is as defined above;
xe2x80x94SORd, wherein Rd is as defined above;
xe2x80x94SRc, wherein Rc is as defined above;
xe2x80x94SO2NRaRf, wherein Rf and Ra are as defined above;
xe2x80x94SO2ORa, wherein Ra is as defined above;
xe2x80x94CONRcRa, wherein Rc and Ra are as defined above;
xe2x80x94OCONRfRa, wherein Rf and Ra are as defined above;
Dxe2x80x2 is situated in the ortho, meta or para position (preferably Dxe2x80x2 is situated in the ortho or meta position) and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, xe2x80x94CN, xe2x80x94NO2,
xe2x80x94NRfRb, wherein Rf and Rb are as defined above;
xe2x80x94ORf, wherein Rf is as defined above;
xe2x80x94OSO2Rd, wherein Rd is as defined above;
Dxe2x80x3 is situated in the ortho, meta or para position (preferably Dxe2x80x3 is situated in the ortho or meta position) and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, xe2x80x94CN, xe2x80x94NO2,
xe2x80x94NRfRb wherein Rf and Rb are as defined above;
xe2x80x94ORf, wherein Rf is as defined above;
xe2x80x94OSO2Rd, wherein Rd is as defined above.
For ease of reference the definitions of formula I above is henceforth referred to as defined in Category A. Unless otherwise stated the definitions of the various substituents are as defined under Category A throughout the present application.
The compounds of the formula I are surprisingly effective in conditions associated with insulin resistance.
Category A2: preferred compounds of the present invention are those of formula I as defined above in category A, but wherein A is situated in the meta or para position (preferably A is situated in the para position) and represents 
wherein R is
xe2x80x94BRa wherein Ra is as defined above;
xe2x80x94SCORa wherein Ra is as defined above;
xe2x80x94OSO2Ra, wherein Ra is as defined above;
R1, R3 and R4 are the same or different and each represents hydrogen, alkyl, aryl, alkenyl, alkynyl or cyano, wherein the alkyl, aryl, alkenyl or alkynyl group is optionally substituted by Rb;
R2 represents represents alkyl, aryl, alkenyl, cyano or alkynyl and wherein the alkyl, aryl, alkenyl and alkynyl group is optionally substituted by Rb; xe2x80x94BRa;
xe2x80x94OSO2Ra, wherein Ra is as defined above;
xe2x80x94OCONRfRa, wherein Rf and Ra are as defined above;
xe2x80x94NRcCOORd, wherein Rc and Rd are as defined above;
xe2x80x94NRcCORa, wherein Rc and Ra are as defined above;
xe2x80x94CONRc wherein Rc is as defined above;
n is an integer from 1 to 2;
m is 1;
D is situated in the ortho, meta or para position (preferably D is situated in the para position) and represents alkyl, acyl, aryl, alkylaryl, halogen, xe2x80x94CN, xe2x80x94NO2, wherein the alkyl group is optionally substituted by Rb.
xe2x80x94ORa, wherein Ra is as defined above;
xe2x80x94OSO2Rd, wherein Rd is as defined above;
xe2x80x94OCONRaRf, wherein Ra and Rf are as defined above;
xe2x80x94NRcCOORa, wherein Rc and Ra are as defined above;
xe2x80x94NRcCORa, wherein Rc and Ra are as defined above;
xe2x80x94SO2Rd, wherein Rd is as defined above;
xe2x80x94SRc, wherein Rc is as defined above;
xe2x80x94CONRaRc, wherein Ra and Rc are as defined above;
xe2x80x94NRcRa, wherein Rc and Ra are as defined above;
Dxe2x80x2 is situated in the ortho, meta or para position (preferably Dxe2x80x2 is situated in the ortho or meta position) and represents hydrogen, alkyl, alkylaryl, halogen, xe2x80x94CN or xe2x80x94NO2;
xe2x80x94ORh, wherein Rh is hydrogen or alkyl;
Dxe2x80x3 is situated in the ortho, meta or para position (preferably Dxe2x80x3 is situated in the ortho or meta position) and represents
hydrogen, alkyl, alkylaryl, halogen, xe2x80x94CN or xe2x80x94NO2;
xe2x80x94ORf, wherein Rf is as defined above.
Category A3: further preferred compounds of the present invention are those as defined within Category A2, but wherein
A is situated in the meta or para position (preferably A is situated in the para position);
R is xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SCORa or xe2x80x94OSO2Ra wherein Ra is hydrogen, alkyl or alkylaryl;
R2 is cyano,
xe2x80x94ORa wherein Ra is as defined above;
xe2x80x94NRcCORa wherein Ra and Rc are as defined above;
xe2x80x94CONRcRa wherein Ra and Rc are as defined above;
R1, R3 and R4 are independently selected from hydrogen or alkyl (preferably both R1, R3 and R4 are hydrogen);
D is situated in the ortho, meta or para position (preferably D is situated in the para position) and represents alkyl optionally substituted by Rb or cyano;
xe2x80x94ORa, wherein Ra is as defined above.
xe2x80x94NRcCORa, wherein Ra and Rc are as defined above;
xe2x80x94CONHRcRa, wherein Ra and Rc are as defined above;
xe2x80x94NRcCOORa, wherein Rc, and Ra are as defined above;
xe2x80x94OSO2Ra, wherein Ra is defined above;
xe2x80x94SO2Rd, wherein Rd is defined above;
xe2x80x94OCONRcRa, wherein Rc, and Ra are as defined above;
Dxe2x80x2 is hydrogen.
Dxe2x80x3 is hydrogen.
Category A4: further preferred compounds of the present invention are those as defined within Category A3, but wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
xe2x80x94SCORa wherein Ra is as defined above;
xe2x80x94OSO2Rd wherein Rd is as defined above;
R1 is hydrogen;
R2 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
R3 is hydrogen;
R4 is hydrogen;
n is the integer 1;
D is is situated in the para position, and represents xe2x80x94NRhCOORd, wherein Rh represents hydrogen or alkyl.
CONRaRc wherein Ra and Rc are as defined above;
xe2x80x94SO2Rd wherein Rd is as defined above;
xe2x80x94OSO2Rd wherein Rd is as defined above;
xe2x80x94CN;
xe2x80x94ORa wherein Ra is as defined above;
xe2x80x94alkyl.
Category A5: further preferred compounds of the invention are those described in Category A4, but wherein
R is
xe2x80x94ORa wherein Ra is as defined above;
R2 is xe2x80x94Oalkyl, preferably xe2x80x94Oloweralkyl;
D is
xe2x80x94NRbCOORa, wherein Rb and Ra are as defined above;
xe2x80x94CN;
xe2x80x94OSO2Rd wherein Rd is as defined above;
Category A5: further preferred compounds of the invention are those described in examples 1 to 13.
Category A6: further preferred compounds of the present invention are compounds which are one of the possible enantiomers.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d, where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically-acceptable salt of a compound of Formula I is, for example, an acid-addition salt of a compound of Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt,
or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
In vivo hydrolysable esters of the compounds of Formula I are just one type of prodrug of the parent molecule. Other prodrugs of the parent molecule are envisaged such as amide prodrugs, and can be prepared by routine methodology well within the capabilities of someone skilled in the art. Prodrugs of the compound of Formula I are within the scope of the invention. Various prodrugs are known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology. 42: 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 xe2x80x9cDesign and Application of Prodrugsxe2x80x9d, by H. Bundgaard p.113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and
e) N. Kakeya, et al., Chem Pharm Bull, 32:692 (1984).
The preferred examples of prodrugs include in vivo hydrolysable esters of a compound of the Formula I. Suitable pharmaceutically-acceptable esters for carboxy include C1-8 alkyl esters, C5-8 cycloalkyl esters, cyclic amine esters, C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxycarbonyloxyC1-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl wherein alkyl, cycloalkyl and cyclicamino groups are optionally substituted by, for example, phenyl, heterocyclcyl, alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy, aryloxy or benzyloxy, and may be formed at any carboxy group in the compounds of this invention.
It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms.
When the substituent ORa represents an alkylaryl group, the preferred alkylaryl is benzyl.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates. Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC. The diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography. Alternatively the stereoisomers may be made by chiral synthesis from chiral starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention.
The following definitions shall apply throughout the specification and the appended claims.
Unless otherwise stated or indicated, the term xe2x80x9calkylxe2x80x9d denotes either a straight or branched alkyl group having from 1 to 6 carbon atoms or a cyclic alkyl atom having from 3 to 6 carbon atoms, the alkyl being substituted or unsubstituted. The term xe2x80x9clower alkylxe2x80x9d denotes either a straight or branched alkyl group having from 1 to 3 carbon atoms or a cyclic alkyl having 3 carbon atoms, the alkyl being substituted or unsubstituted. Examples of said alkyl and lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl as well as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred alkyl groups methyl, ethyl, propyl, isopropyl and tertiary butyl.
Unless otherwise stated or indicated, the term xe2x80x9calkoxyxe2x80x9d denotes a group O-alkyl, wherein alkyl is as defined above.
Unless otherwise stated or indicated, the term xe2x80x9chalogenxe2x80x9d shall mean fluorine, chlorine, bromine or iodine, preferably fluorine.
Unless otherwise stated or indicated, the term xe2x80x9carylxe2x80x9d denotes a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, or a fused ring system of any of these groups, such as naphthyl.
Unless otherwise stated or indicated, the term xe2x80x9csubstitutedxe2x80x9d denotes an alkyl or an aryl group as defined above which is substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, aryl or cyano groups.
Unless otherwise stated or indicated, the term xe2x80x9calkylarylxe2x80x9d denotes a 
wherein n is an integer 1 to 6 and Rr and Ri are the same or different and each represents hydrogen or an alkyl or aryl group as defined above.
Unless otherwise stated or indicated, the term xe2x80x9cacylxe2x80x9d denotes a group 
wherein Rj is hydrogen, alkyl, alkoxy, aryl and alkylaryl as defined above.
Unless otherwise stated or indicated, the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d denote a straight or branched, substituted or unsubstituted unsaturated hydrocarbon group having one or more double or triple bonds and having a maximum of 6 carbon atoms, preferably 3 carbon atoms.
Unless otherwise stated or indicated the term xe2x80x9cprotective groupxe2x80x9d denotes a protecting group as described in the standard text xe2x80x9cProtecting groups in Organic Synthesisxe2x80x9d, 2nd Edition (1991) by Greene and Wuts. The protective group may also be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin.
Methods of Preparation
The compounds of the invention may be prepared as outlined below according to any of the following methods. However, the invention is not limited to these methods, the compounds may also be prepared as described for structurally related compounds in the prior art.
A. The compounds of Formula I wherein R or R2 is, where defined, xe2x80x94ORd, xe2x80x94SCORd, xe2x80x94SRd, xe2x80x94OSO2Rd, NRcCOORa, NRcCORa, xe2x80x94NRaCONRaRk or xe2x80x94NRcSO2Rd can be prepared by reaction of a compound of Formula I wherein the respective R or R2 group is, for example, xe2x80x94OH, xe2x80x94SH or xe2x80x94NHRa with a suitable reagent, such as a thioate, a sulfonyl halide, an isocyanate, a chlorofortnate or an addition reagent for ether, such as alkylhalide or arylhalide. The reactions can be carried out in accordance with methods known to those skilled in the art, or as described in the examples. Suitable references are
xe2x80x9cComprehensive Organic Transformationsxe2x80x9d R. C. Larock (VCH Publishers Inc.) 1989, p445-448, for the formation of alkyl or aryl ethers.
xe2x80x9cAdvanced Organic Chemistryxe2x80x9d J. March (4th edition), John Wiley and Sons, 407-409, for the formation of thioethers, and 498-499, for the formation of sulfonates, 417-418, for the formation of amides, 411-413, for formation of amines.
B. The compounds of Formula I wherein R or R2 is, where defined, xe2x80x94SRa or xe2x80x94SCORa can be prepared by reaction of a compound of Formula I wherein the respective R or R2 group is, for example, xe2x80x94OSO2Ra with a suitable reagent, respectively. YSRa or YSCORa (wherein Y is a cation). Suitably the reaction is carried out in an inert solvent, such as DMF or methanol at room temprature with a suitable reducing agent, such as sodium borohydride, LiAlH4, DIBAH or borane methylsulfide.
C. The compounds of Formula I, wherein X is 1, can be prepared by a reduction reaction of a compound of Formula II, 
wherein, K is xe2x80x94ORa or xe2x80x94NRaRa. The reaction is ideally carried out in an inert solvent, such as THF or methanol, and ideally at reduced temprature. Suitable reducing agents are those known to reduce carbonyl groups, such as, NaBH4, DIBAH, LiAlH4.
The compounds of formula IIa and IIb, wherein K is xe2x80x94NRaRa may be prepared from the respective compounds of formula IIA and IEBK wherein K is xe2x80x94ORa. The reactions can be carried out in accordane with methods known to those skilled in the art, or as described in the examples. Suitable references are found in Advanced Organic Chemistryxe2x80x9d J. March (4th edition), John Wiley and Sons, 419-424.
The compounds of formula IIa can be prepared by an alkylation reaction with a compound of formula VIII 
where X is a leaving group, such as halogen, a sulfonate or triflate, and a compound of formula IXa 
in which D, Dxe2x80x2, Dxe2x80x3, R1, R2, R3, R4, m, and n, are as defined in Category A and, if desired, followed by removal of any protective groups.
In the alkylation step the compound of Formula IXa is reacted with a compound of formula VIII in the presence of one or more bases such as potassium carbonate, triethylbenzylammonium chloride, sodium hydride, LDA, butyllithium or LHMDS and in a inert solvent such as acetonitrile, DMF or dichloromethane at a suitable temperature and time. The reaction can be carried out as described in the examples or by standard methods known in the literature (Synth. Comm. 19(788) 1167-1175 (1989)). C1. The compounds of Formula I wherein R, D or R2 is cyano may be prepared by the dehydration of a compound of Formula I wherein the respective R, D or R2 group is xe2x80x94CONH2, such as compounds of Formula II where K is xe2x80x94NH2. Ideally the reaction is carried out with an inert solvent, such as DMF or methanol at room temperature. The reagent is a suitable dehydrating agent such as trifluoroacetic anhydride. The reaction may be carried out according to analagous methods described in the literature, such as, Synthesis (1992) Falorni M. et al., 972-976 and J.Org.Chem. (1996), Heck M. P. et al., 61(19), 6486.
The compounds of Formula II can be prepared by a condensation reaction, such as a Knoevenagel or Wittig type reaction, of an aldehyde compound of the Formula III 
with a compound of the Formula IV or V 
the anion is preferably a halogen such as chlorine or bromine, in which formulas D, Dxe2x80x2, Dxe2x80x3, m, n, R1, R2 and R4 are as defined in Category A, X is 1, and L1xe2x95x90L2xe2x95x90L3 are phenyl or L1xe2x95x90L2 are ORd (wherein Rd is as defined in Category A) and L3 is xe2x95x90O, followed by reduction of the double bond, if necessary to form the saturated compound of formula I, and removal of protective groups.
Approximately equimolar amounts of reactants are mixed in the presence of a base, such as sodium acetate, piperidine acetate, LDA or potassium tert-butoxide to provide the compound of formula I wherein A is the unsaturated moiety. This step may be carried out in the presence of an inert solvent or in the absence of solvent in which case the temperature should be sufficiently high to cause at least partial melting of the reaction mixture, a preferred such temperature is in the range of 100xc2x0 C. to 250xc2x0 C.
Where R4 is not hydrogen it is necessary to add a dehydroxylating agent in order to remove the formed xe2x80x94OH at the xcex2 carbon. Suitable reaction conditions and reagents are described in Synthetic Communications Smonou I et al., (1988) 18, 833, and Synthesis Olag G. Et al., (1991) 407, and J.Heterocyclic Chemistry Georgiadis, M. P. Etal., (1991) 28(3), 599-604, and Synth. Commun. Majeticj, G. et al. (1993), 23(16), 2331-2335, and Bioorg. Med. Chem. Lett. (1998) 8(2), 175-178.
Sometimes it is necessary, when R4 is H, to add a dehydrating agent such as p-toluenesulfonic acid in order to achieve the formation of the double bond. In a typical such reaction the starting material of formula III and the compound of formula IV are combined in approximately equimolar amounts and molar excess, preferably 1-5 fold, of anhydrous sodium acetate and the mixture is heated until it melts if necessary under vacuum. The compound of formula IIb can then be isolated by mixing with water and acetone, followed by filtration of the formed precipitate. The crude product can be purified if desired, e.g. by recrystallization or by standard chromatographic methods.
This reaction can also be performed conveniently in a solvent such as toluene in the presence of piperidine acetate. The reaction mixture is refluxed in a Dean-Stark apparatus to remove water. The solution is then cooled and the olefin product isolated and purified,
by standard methods.
The reaction can also be performed by mixing the starting material and the compound of formula V in dry THF, slowly adding potassium tert-butoxide at xe2x88x9220xc2x0 C. and quenching the reaction with acetic acid. The crude product is isolated and then dissolved in toluene and refluxed with p-toluenesulfonic acid in a Dean-Stark apparatus to remove the water. The product is then isolated and purified, by standard methods.
The reaction can also be performed in the presence of titanium (IV) chloride and pyridine in an inert solvent, such as chloroform.
The condensation step could also be performed as a Wittig-type reaction (cf. with a compound of formula IV Comprehensive Organic Synthesis vol. 1 p. 755-781 Pergamon Press).
Approximately equimolar amounts of reactants III and IV, are mixed in the presence of a base such as tetramethylguanidine or potassium carbonate in a 1-5 fold molar excess. This reaction may be carried out in the presence of an inert solvent such as dichloromethane or isopropanol at a suitable temperature (xe2x88x9210xc2x0 C. to +60xc2x0 C.) and at a time long enough.
The compound of the formula III is prepared by coupling a compound of the formula VI 
with a compound of the formula VII 
in which formulas D, Dxe2x80x2, Dxe2x80x3, R1, m and n are as defined in Category A, at, for example alkylation conditions or by a Mitsunobu reaction (Tsunoda, Tetr. Lett. 34, 1639-42 (1993), when necessary followed by modifications of the D-groups as described in the experimental section.
The group Z can be xe2x80x94OH or a leaving group, such as halogen, sulfonate or triflate. The alkylation reaction and the Mitsunobu reaction can be carried out as described below or as in the experimental section.
The compounds of formula IV, V, VI and VII are either commercially available or can be prepared by standard procedures known to anyone skilled in the art from commercially available starting materials or by analagous procedures described in this application.
D. The reduction of the olefin version of the compound of formula I to the saturated version of a compound of formula I may be carried out by using a wide variety of reducing methods known to reduce carbonxe2x80x94carbon double bonds, such as catalytic hydrogenation in the presence of an appropriate catalyst, magnesium or sodium amalgam in a lower alcohol such as methanol, or hydrogen transfer reagents such as diethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
The catalytic hydrogenation can be conducted in alcohol, cellosolves, protic polar organic solvents, ethers, lower aliphatic acids, and particularly in methanol, ethanol, methoxyethanol, dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate or acetic acid, either used alone or in mixture. Examples of the catalyst used include palladium black, palladium on activated charcoal, platinum oxide or Wilkinson""s catalyst. The reaction can proceed at different temperatures and pressures depending on the reactivity of the aimed reaction.
In case of hydrogen transfer reaction with diethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, equimolar amounts of reactants are mixed and the mixture is warmed to melting (140xc2x0 C.-250xc2x0 C.) under inert atmosphere or under vacuum.
E. The compounds of the invention of formula I can be prepared by an alkylation reaction with a compound of formula VIII 
where X is a leaving group, such as halogen, a sulfonate or triflate, and a compound of formula IXb 
in which formulas D, D1 R1, R2, R3, R4, n, x, and Dxe2x80x3, are as defined in Category A and, if desired, followed by removal of any protective groups.
In the alkylation step the compound of Formula IX is reacted with a compound of formula VIII in the presence of one or more bases such as potassium carbonate, triethylbenzylammonium chloride, sodium hydride, LDA, butyllithium or LHMDS and in a inert solvent such as acetonitrile, DMF or dichloromethane at a suitable temperature and time. The reaction can be carried out as described in the examples or by standard methods known in the literature (Synth. Comm. 19(788) 1167-1175 (1989)).
The compound of Formula VIII can be prepared from an alcohol of formula X 
wherein D, Dxe2x80x2, Dxe2x80x3 R1, R3 and n are as defined in Category A using standard methods.
The compound of Formula X can be prepared from a compound of Formula III either by reduction with a reducing agent known to convert a carbonyl group to a hydroxyl group such as lithium borohydride or sodium borohydride or by reaction with an organometallic compound such as an organolithium or a Grignard reagent by standard methods.
F. The compounds of the invention of Formula I can be prepared by reaction of a compound of formula VI with a compound of the Formula XI 
in which formulas D, Dxe2x80x2, Dxe2x80x3, R1, R2, R3, R4, m,n, x and R are as defined in Category A, in a similar reaction as described above, additional protective groups may be necessary.
The compound of Formula XI can be prepared in accordance to method C from commercially available starting materials and compounds of formula IV or V.
The reaction is carried out according to standard procedure for an alkylation or Mitsunobu reaction.
F1. In an alkylation reaction the leaving group Z of the compound of formula VI can be a sulfonate such as mesylate, nosylate, tosylate, or a halogen, such as bromine or iodine. The compounds of Formula VI and XI, in approximately equimolar amounts or with an excess of one of the compounds, are heated to reflux temperature in an inert solvent, such as isopropanol or acetonitrile, in the presence of a base, such as potassium carbonate or cesium carbonate.
The mixture is refluxed for the necessary time, typically between 0.5 h to 24 h, the work up procedure usually include filtration, for removal of solid salt, evaporation and extraction with water and an organic solvent such as dichloromethane, ethyl acetate, or diethyl ether.
The crude product is purified if desired e.g. by recrystallization or by standard chromatographic methods.
F2. The Mitsunobu reaction can be carried out according to standard methods. In a typical Mitsunobu reaction a compound of Formula VI, wherein the group F of the compound of Formula VI is a hydroxyl group, and a compound of formula XI are mixed, in approximately equimolar amounts or with an excess of one of the compounds, in an inert solvent, such as chloroform, dichloromethane, or THF. A slight molar excess of an azodicarboxylate, (1-4 equivalents) such as DEAD or ADDP and a phosphine (1-4 equivalents), such as tributylphosphine or triphenylphosphine are added and the reaction mixture is stirred at a temperature high enough, for example room temperature, and a time long enough (1-24 hours) to obtain the crude product, which can be worked up according to standard literature methods and if desired purified, e.g. by standard chromatographic methods.
G. The compounds of the invention of Formula I wherein D is xe2x80x94OSO2Rd, xe2x80x94SRc, xe2x80x94OCONRfRa, xe2x80x94NRcCOORa, xe2x80x94NRcCORa, NRcRd, xe2x80x94NRcCONRaRd, NRcSO2Rd and xe2x80x94NRcCSNRaRk, wherein Ra, Rc, Rd, Rf and Rk are as defined in Category A, can be prepared by reacting a compound of Formula XI 
wherein Dxe2x80x2, Dxe2x80x3, n and A are as defined in Category A and X1xe2x95x90xe2x80x94OH, xe2x80x94SH or xe2x80x94NRcH, with a suitable reagent, such as a sulfonylhalide, isocyanate, acylhalide, chloroformate, anhydride or an alkylhalide in an inert solvent such as dichloromethane or toluene and when necessary in the presence of a base, such as triethylamine or pyridine and eventually followed by removal of protective groups.
The reaction can be carried out in accordance with methods known to those skilled in the art.
H. The compounds of the invention of Formula I where D is xe2x80x94SO2Rd or xe2x80x94SORd, wherein Rd is as defined in Category A, can be prepared by oxidizing a compound of formula 
wherein Dxe2x80x2, Dxe2x80x3, n and A are as defined in Category A and X2 is xe2x80x94SORd or xe2x80x94SRd, wherein Rd is as defined in Category A,
with oxidizing agents such as m-chloroperoxybenzoic acid or hydrogen peroxide in an inert solvent such as dichloromethane eventually followed by removal of protective groups. Compounds of Formula XIV where R contains a xe2x80x94Sxe2x80x94 or xe2x80x94SOxe2x80x94 group should not be used unless oxidation of such groups is required.
The reactions can be carried out according to standard procedures or as described in the experimental section.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative and in some occasions, more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction).
In any of the preceding methods of preparation Axe2x80x94H, where necessary, hydroxy, amino or other reactive groups may be protected using a protecting group, as described in the standard text xe2x80x9cProtective groups in Organic Synthesisxe2x80x9d, 2nd Edition (1991) by Greene and Wuts. The protecting group may also be a resin, such as Wang resin or 2-chlorotrityl chloride resin. The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore. Protecting groups may be removed in accordance to techniques which are well known to those skilled in the art.
The expression xe2x80x9cinert solventxe2x80x9d refers to a solvent which does not react with the starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
Pharmaceutical Preparations
The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways; buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient either as a free acid, or a pharmaceutically acceptable organic or inorganic base addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with other therapeutic agents which are useful in the treatment of disorders associated with the development and progress of atherosclerosis such as hypertension, hyperlipidemias, dyslipidemias, diabetes and obesity. Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight.
According to a further aspect of the invention there is also provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
Pharmacological Properties
The present compounds of formula (I) are useful for the prophylaxis and/or treatment of clinical conditions associated with reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders. These clinical conditions will include, but will not be limited to, abdominal obesity, arterial hypertension, hyperinsulinaemia, hyperglycaemia, type 2 diabetes mellitus and the dyslipidaemia characteristically appearing with insulin resistance. This dyslipidaemia, also known as the atherogenic lipoprotein profile, phenotype B, is characterised by moderately elevated non-esterified fatty acids, elevated very low density lipoproteins (VLDL) triglyceride rich particles, low high density lipoproteins (HDL) particle levels cholesterol and the presence of small, dense, low density lipoprotein (LDL) particles. Treatment with the present compounds is expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis. These cardiovascular disease conditions include macro-angiophaties causing myocardial infarction, cerebrovascular disease and peripheral arterial insufficiency of the lower extremities. Because of their insulin sensitizing effect the compounds of formula I are also expected to prevent or delay the development of type 2 diabetes and thus reduce the progress of clinical conditions associated with chronic hyperglycaemia in diabetes type 1 such as the micro-angiophaties causing renal disease, retinal damage and peripheral vascular disease of the lower limbs. Furthermore the compounds may be useful in treatment of various conditions outside the cardiovascular system associated with insulin resistance like polycystic ovarian syndrome.